The dopamine receptor system plays a key role in numerous neuropsychiatric and neurological disorders and investigation into mechanistic underpinnings and neuroadaptations within this family of receptors has been the focus of intensive research over the past decade. The dopamine D3 receptor subtype has been hypothesized to play a fundamental role, for example, in the abuse-related effects of cocaine and other drugs of abuse. Hence, there is a well recognized need to develop novel, selective and bioavailable dopamine D3 receptor ligands.
Further reasons for pursuing dopamine D3 receptor selective ligands as medications for various conditions come from the brain localization of D3 receptors, which are primarily expressed in limbic regions of the brain, including the nucleus accumbens. D3 receptor blockade may attenuate drug reward and/or reinforcement while avoiding the risk of extrapyramidal side effects associated with the blockade of the more ubiquitous D2 receptors.
The high degree of amino acid homology within the binding sites of the dopamine D2-like receptors, and especially between the D2 and D3 dopamine receptor subtypes, has provided a formidable challenge in the pursuit to discover dopamine D3-selective compounds. Thus far, high dopamine D2/D3 selectivity has generally been achieved with relatively large molecules, characterized, for example, by a heterocyclic moiety bridged by an unsubstituted 4-carbon chain, or carbocycle to an extended or substituted arylamide or a corresponding bioisotere.
In addition to optimizing pharmacological selectivity, it is also important that dopamine D3-selective compounds be able to penetrate the blood brain barrier (BBB) and have appropriate pharmacokinetics to facilitate interpretation of in vivo results. However, generally relatively high doses of D3-selective agents have been required for behavioral activity. It is not known whether these required high doses are due to a low permeability surface area product of these agents for crossing the BBB, high peripheral metabolism, large uptake in some other organ or compartment, or is due to some other reason.
Therefore, there is a well recognized need in the art for highly D3-selective compounds that are able to penetrate the blood brain barrier, and that show activity at relatively low dosages.